Abstract
Serum is an abundant and accessible source of circulating extracellular vesicles (EVs). Serum-EV (sEV) pro-angiogenic capability and mechanisms are herein analyzed using an in vitro assay which predicts sEV angiogenic potential in vivo. Effective sEVs (e-sEVs) also improved vascular remodeling and prevented muscle damage in a mouse model of acute hind limb ischemia. e-sEV angiogenic proteomic and transcriptomic analyses show a positive correlation with matrix-metalloproteinase activation and extracellular matrix organization, cytokine and chemokine signaling pathways, Insulin-like Growth Factor and platelet pathways, and Vascular Endothelial Growth Factor signaling. A discrete gene signature, which highlights differences in e-sEV and ineffective-EV biological activity, was identified using gene ontology (GO) functional analysis. An enrichment of genes associated with the Transforming Growth Factor beta 1 (TGFβ1) signaling cascade is associated with e-sEV administration but not with ineffective-EVs. Chromatin immunoprecipitation analysis on the inhibitor of DNA binding I (ID1) promoter region, and the knock-down of small mother against decapentaplegic (SMAD)1–5 proteins confirmed GO functional analyses. This study demonstrates sEV pro-angiogenic activity, validates a simple, sEV pro-angiogenic assay which predicts their biological activity in vivo, and identifies the TGFβ1 cascade as a relevant mediator. We propose serum as a readily available source of EVs for therapeutic purposes.
Highlights
Serum is an abundant and accessible source of circulating extracellular vesicles (EVs)
EVs are currently those released by stem cells, thanks to their ability to mimic the effects of the cell of origin[14]
EV biological activity has been linked to the transfer of bioactive lipids, proteins, receptors, mRNAs and miRNAs that may change the phenotype and function of recipient cells[36,37,38]
Summary
Serum is an abundant and accessible source of circulating extracellular vesicles (EVs). This study demonstrates sEV pro-angiogenic activity, validates a simple, sEV pro-angiogenic assay which predicts their biological activity in vivo, and identifies the TGFβ1 cascade as a relevant mediator. Surgical or endovascular intervention are still the standard therapy for improving blood flow[2], most patients complain of persistent or recurring symptoms even after successful revascularization[3]. This implies that new therapeutic options for patients complying these symptoms are very much still a major unmet need. The transfer of EV cargo, including nucleic acids and proteins, into recipient cells is the most relevant mechanism of EV action[13, 14].
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